The long term objectives of this program are to elucidate the pathogenesis of liver cell injury and hepatocellular carcinoma following hepatitis C virus (HCV) infection. In order to achieve these objectives we will develop a transgenic animal model in which HCV core (C), HCV envelope 1 (E1) and HCV envelope 2 (E2/NS1) proteins are expressed in the liver under the transcriptional control of liver specific promoters, such as albumin, metallothionein and major urinary protein (MUP). In these studies we will test the alternate hypotheses that liver disease following HCV infection is caused either by the direct cytopathic effect of one or more HCV gene products, or by a cellular immune response to these products. To this end we will characterize the intracellular distribution of each HCV structural protein, as well as its ability to cause hepatocyte injury. In immunological studies, the repertoire of cytotoxic T cell responses to each of the viral antigens will be defined in order to determine which of the viral gene products are important with respect to the induction of hepatocellular injury. The conditions necessary to induce severe, chronic immunologically mediated liver cell injury will be established in order to determine whether such a disease will lead to the development of hepatocellular carcinoma. We anticipate that these studies will lead to a better understanding of the pathogenesis of liver cell injury and hepatocellular carcinoma due to HCV infection, and to the identification of T cell epitopes which will contribute to the development of T cell based vaccines for the prevention of HCV infection and possibly the establishment of novel immunotherapeutic strategies for the termination of HCV induced chronic liver disease.